CN106674298A - Synthesis method of alpha-GalCer analogue containing fluorine atom and having immunoregulatory activity - Google Patents
Synthesis method of alpha-GalCer analogue containing fluorine atom and having immunoregulatory activity Download PDFInfo
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- CN106674298A CN106674298A CN201510766031.2A CN201510766031A CN106674298A CN 106674298 A CN106674298 A CN 106674298A CN 201510766031 A CN201510766031 A CN 201510766031A CN 106674298 A CN106674298 A CN 106674298A
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- galcer
- fluorine atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Abstract
The invention discloses a synthesis method of alpha-GalCer analogue containing fluorine atom and having immunoregulatory activity, and belongs to the technical field of chemistry and medicine. In the synthesis method, the glycosyl part adopts galactose or galactose in a saccharide ring with oxygen atom being replaced by oxygen atom, an R1 position is replaced by fluorine atom, and meanwhile an R2 position is replaced by various substituent groups, so that the alpha-GalCer analogue is obtained, and a method is provided for obtaining alpha-GalCer analogues with better immunoregulatory activity and biological activity, such as cancer resistance and tumour resistance. The method is characterized by comprising the following steps.
Description
Technical field
The present invention relates to have the new alpha-galactosylceramide of immunoregulatory activity (α-GalCer) analog and preparation method, belong to
In chemistry and pharmaceutical technology field.
Background technology
Yasuhiko Koezuka research groups were in a series of isolated glycosyl sphingolipid class compounds from spongy tissue in 1994
Agelasphin.Subsequent research finds that in this series compound α-GalCer have extensive potential source biomolecule activity, such as disease-resistant
Poison, antitumor, the effect such as antiinflammatory and treatment autoimmune disease, this makes to which give very big concern.
Current research thinks that the immunostimulation mechanism of α-GalCer is that α-GalCer can be combined by the identification of CD1d albumen, shape
Into the binary complex of CD1d and α-GalCer, and then recognized by the φt cell receptor on NKT cell surfaces, form three
First complex, so as to activate NKT cells, produces immunne response so that NKT cells secrete rapidly the substantial amounts of Th1 of release and
Th2 type cytokines.But, the antagonism of Th1 and Th2 type cytokines causes exclusive use α-GalCer to treat certain
The therapeutic effect of disease is bad.Accordingly it is desirable to NKT cells can be realized by carrying out structural modification to α-GalCer
Optionally break up Th1 and Th2, while probing into the structure activity relationship of α-GalCer analog.
In recent years, numerous chemists had obtained the analog of substantial amounts of α-GalCer by the method such as complete synthesis and semi-synthetic.
Modification to glycosidic bond, the structural modification to ceramide, the structure to fat chain are repaiied mainly to be included to the structure of modification of α-GalCer
It is decorated with and the structural modification to glycosyl.Wherein it is mostly alkyl chain, hydroxyl isopolarity on modified plant sphingol chain
Group, and galactose is modified.Also there is the oxygen atom to glycosidic bond to carry out replacement and obtain carbon glycosides, sulfur glycosides etc..Wherein one
α-GalCer the analog of a little synthetic shows the life for preferably breaking up Th1 and Th2 induction NKT cell selectives
Thing effect.
At present, for the epoxy of the galactosyl moieties in α-GalCer replaces with the less report of sulfur, while its aliphatic chain is complete
Fluorine replaces or terminal methyl group is not yet had been reported that by the derivant of fluoro.In view of the epoxy of glycosyl part is replaced with into sulphur atom not only
Such compound can be increased to internal acid or alkali environment stability and to change such compound mutual with internal associated protein
Effect, while the chain alkyl perfluor replacement of such compound or terminal methyl group fluoro can be changed into such compound and surrounding
The binding ability of aminoacid, the oxygen atom in the galactose sugar ring in α-GalCer is replaced with sulphur atom by us, while by fat
Chain perfluor replaces or by terminal methyl group fluoro, obtains some α-GalCer analog with good biological activity.
The content of the invention
The purpose of the present invention is to carry out structural modification by the glycosyl to α-GalCer and its fat chain part can effectively induce to obtain
The analog of the α-GalCer of cell selective ground differentiation Th1 and Th2.
The structure activity study of α-GalCer is shown, galactose moiety is that α-GalCer and the like activity expression needs glucosides
Key keeps α configurations.Some the α-GalCer's for having synthesized at present plays work like thing is all more or less in the balance of Th1/Th2
With, but be the failure to the release cytokine of the selectivity required for reaching and affect the expression of its biological activity.We are by by sugared ring
In oxygen replace with S, while by aliphatic chain perfluor replace or by terminal methyl group fluoro, to improving the specificity of cytokine
Release, so as to improving its antitumor, adjusting the biological activitys such as immunocompetence, by bioactivity screening, finds activity preferably
Lead compound.The technical solution of the present invention is, novel alpha-GalCer analog and synthetic method, it is characterised in that
Compound has following structure：
Wherein, X is O or S；Substituent R1Selected from C3F7To C17F35Saturated chain, terminal methyl group by single fluorine atom/
The direct-connected alkane of saturation of 3 to 25 carbon of two fluorine atom/tri- fluorine atom replacements；Substituent R2Select to C7H15To C25H51
Saturated straight chain.
The preparation method of novel alpha-GalCer analog, it is characterised in that the method comprises the following steps：
The concrete synthesis step of above-mentioned route is：
(1) condensation reagent can select 2- (7- azo BTAs)-N, N, N', N'- tetramethylurea in the preparation process of intermediate 3
Hexafluorophosphoric acid ester (HATU), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (EDCI)/1- hydroxy benzeness
And triazole (HOBt), 1- n-pro-pyl phosphoric anhydrides (T3P) etc., preferred HATU.
(2) intermediate 3 obtains intermediate 4 with tert-butyl diphenyl chlorosilane reaction.
(3) intermediate 4 obtains intermediate 5 with Benzenecarbonyl chloride. reaction.
(4) intermediate 5 can obtain intermediate 6 in the presence of Fluohydric acid. pyridine complex or tetrabutyl ammonium fluoride.
(5) receptor 6 and donor 7 react under catalyst action and obtain coupled product 8, and when X is Cl, Br, catalyst can
Think potassium carbonate, Disilver carbonate, cesium carbonate, carbonic acid hydrargyrum, silver perchlorate, mercuric perchlorate and silver trifluoromethanesulfonate etc..Work as X
For OAc when, catalyst can be for mercury dibromide, ferric chloride, titanium tetrachloride, stannum dichloride and butter of tin etc..When
When X is SEt, SPh, reaction condition is N- N-iodosuccinimides (NIS) and catalyst trifluoromethanesulfonic acid, boron trifluoride
Ether, trifluoromethanesulfonic acid trimethyl silicone grease, trifluoromethanesulfonic acid triethyl group silicone grease, tert-butyl group dimethyl silyl triflate etc..
When X is OC (NH) CCl3When, catalyst can be boron trifluoride diethyl etherate, trifluoromethanesulfonic acid trimethyl silicone grease, fluoroform sulphur
The custom catalystses such as triethylenetetraminehexaacetic acid base silicone grease, tert-butyl group dimethyl silyl triflate.Solvent can for dichloromethane, ether,
The organic solvents such as tetrahydrofuran, toluene.
(6) the Jing deprotections of intermediate 8 obtain α-GalCer analog.Wherein R3Can be acetyl group, benzoyl, benzyl
Etc. protection group, deacylation base protective condition can be the alkali such as Feldalat NM, potassium carbonate, sodium hydroxide, and debenzylation protective condition can be with
For hydrogen/palladium carbon, hydrogen/palladium dydroxide etc..
The advantage of the route is：Reaction condition is gentle, easy to operate, can be used in preparation of industrialization.Synthetic route can be used in
Prepare different types of α-GalCer analog.
Embodiment：
1. embodiments of the invention presented below (by taking as above compound as an example)：
The synthesis of compound 3：Under room temperature, during perfluoro caprylic acid (1eqv) is placed in into DMF solution, phytosphingosine (1.2 is sequentially added
Eqv), 2- (7- azo BTAs)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HATU) (1.1eqv), DIPEA, instead
12 hours should be continued, water is added, and extracted with ethyl acetate, organic faciess are dried, and are evaporated the crude product for obtaining intermediate 3.
The synthesis of compound 4：During intermediate 3 (1eqv) is dissolved in into pyridine, tert-butyl diphenyl chlorosilane (1.2eqv) is added,
Room temperature reaction 3 hours, is evaporated organic solvent, and column chromatography obtains intermediate 4, and it is 70% to calculate gross production rate from perfluoro caprylic acid.
The synthesis of compound 5：During intermediate 4 (1eqv) is dissolved in into pyridine, Benzenecarbonyl chloride. (5eqv) is added, reacted overnight, plus
Enter water quenching to go out, be extracted with ethyl acetate, saturated sodium bicarbonate washing is dried, and is evaporated, and column chromatography obtains intermediate 5, yield
For 90%.
The synthesis of compound 6：Intermediate 5 is dissolved in dichloromethane, Fluohydric acid. pyridine complex (1eqv), reaction 3 is added
After hour, add saturated sodium bicarbonate solution that reaction is quenched, extracted with dichloromethane, saturated sodium bicarbonate solution washing, saline
Washing, is dried, and is evaporated, and column chromatography obtains intermediate 6, and yield is 90%.
The synthesis of compound 8：Under nitrogen protection, intermediate 6 and full acetyl 5- sulfur galactose Schmidt reagent 7 are added in flask,
Dichloromethane is added, is stirred 10 minutes under the conditions of -10 DEG C, be then added dropwise over boron trifluoride ether solution, continue low-temp reaction
3 hours.After scrubbed, dry, column chromatography for separation obtains compound 8, and yield is 65%.
The synthesis of compound 9 (α-GalCer analog)：Intermediate 8 is dissolved in methanol, plus sodium methoxide solution (1mol/L, 1
Eqv), reaction overnight, adds acidic resins, stirs 0.5 hour, and white solid is separated out, and methanol cleaning obtains final product α-GalCer
Analog 10, yield is 95%.
Claims (7)
1. α-GalCer the analog with immunoregulatory activity of fluorine atom is contained, and its architectural feature is：
Wherein, X is O or S；Substituent R1Selected from C3F7To C17F35Saturated chain, or terminal methyl group is former by single fluorine
The direct-connected alkane of saturation of 3 to 25 carbon that son/two fluorine atom/tri- fluorine atoms replace；Substituent R2Select to C7H15To C25H51
Saturated straight chain and side chain.
2. compound according to claim 1, wherein X represents oxygen atom or sulphur atom.
3. compound according to claim 1, wherein R1Represent and contain in chain 3 to 17 carbon atom perfluoroalkyl chain and attachments.
4. compound according to claim 1, wherein R1Represent terminal methyl group to be taken by single fluorine atom/two fluorine atom/tri- fluorine atom
The direct-connected alkyl of 3 to 25 carbon saturations in generation.
5. compound according to claim 1, wherein R2Represent in chain containing the straight chain saturated alkyl of 7 to 25 carbon atoms.
6. the compound according to claim 1 of medicine is used as.
7. the compound with anti-tumor activity according to claim 1, its preparation is characterised by
Wherein, X is oxygen atom or sulphur atom, and Y is Br, SEt, SPh, OAc and OC (NH) CCl3Etc. substituent group.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107522760A (en) * | 2017-08-21 | 2017-12-29 | 河南师范大学 | With immunocompetent α GalCer phosphate compounds and its synthetic method |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105461681A (en) * | 2014-09-05 | 2016-04-06 | 中国科学院生态环境研究中心 | KRN7000 analogue with antitumor activity and synthetic method thereof |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105461681A (en) * | 2014-09-05 | 2016-04-06 | 中国科学院生态环境研究中心 | KRN7000 analogue with antitumor activity and synthetic method thereof |
Non-Patent Citations (4)
| Title |
|---|
| JINGJING BI,等: "Synthesis and Biological Activities of 5‑Thio-α-GalCers", 《MED. CHEM. LETT.》 * |
| MAN SUN，等: "Design and synthesis of new KRN7000 analogues", 《TETRAHEDRON》 * |
| 冯俊娜，等: "KRN7000 结构类似物及其免疫活性研究进展", 《有机化学》 * |
| 尤启东: "《药物化学》", 31 January 2004, 化学工业出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107522760A (en) * | 2017-08-21 | 2017-12-29 | 河南师范大学 | With immunocompetent α GalCer phosphate compounds and its synthetic method |
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Application publication date: 20170517 |